Possible curative role of curcumin and silymarin against nephrotoxicity induced by gamma-rays in rats

Abstract

Curcumin (CUR) and silymarin (SLM) are powerful antioxidant and anti-inflammatory compounds with beneficial protective effects against renal diseases. The purpose of this study was to evaluate the efficacy of CUR and SLM alone or in combination on radiation (IR) induced kidney injury. The results showed that CUR and SLM alone or in combination attenuated the oxidative stress denoted by a reduction in the level of malondialdehyde (MDA), hydrogen peroxide (H₂O₂) and advanced oxidation protein products (AOPP) along with a marked increase of glutathione GSH content and total antioxidant capacity (TAC). Additionally, a significant decrease in the level of blood urea nitrogen (BUN), creatinine, Cystatin-C (CYT-C), neutrophil gelatinase-associated lipocalin (N-GAL) and Kidney Injury Molecule-1 (Kim-1) was recorded. Moreover, the treatment resulted in a remarkable decline in the serum levels of interleukin-18(IL-18), tumor necrosis factor- alpha (TNF-α), C reactive protein (CRP), BCL2 associated X protein (Bax), Factor-related Apoptosis (FAS) and the activity of Caspase-3 associated by an increase of B-cell CLL/lymphoma 2 (Bcl2) level. The results were confirmed with the histopathological examination. Kidney of irradiated showed glomerular atrophy, massive necrotic changes of expanded tubules with hyaline cast inside some tubules and apoptotic changes were recorded in some renal tubules. While irradiated rats treated with CUR and SLM exhibited marked preservation of the cellular structure of their kidney tissue. In conclusion, the combination of CUR and SLM could be more potent than a single agent on the biochemical and histological changes of the irradiated rat renal tissue.

Introduction

Ionizing radiation (IR) can induce different cellular reactions depending upon rate of exposure and dose (Park et al., 2015). The toxic effects of high-level IR on biological system are largely produced by the excessive production of reactive oxygen species (ROS) that overwhelm the levels of antioxidants. ROS considers as the chief mechanism for radiation–induced nephrotoxicity through lipid peroxidation, protein oxidation, and depletion of anti-oxidant elements (Einor et al., 2016). The kidney is an important organ necessary for the body to do several essential functions such as detoxification, and excretion of toxic metabolites and drugs. Therefore, the kidney can be considered as a major target organ for exogenous toxicants. Kidney is a radiosensitive organ. Histopathological surveys of radiation-induced nephropathy have shown the occurrence of damage to glomeruli, blood vessels, tubular epithelium, and interstitium (Cohen and Robbins, 2003).

It is well known that compounds with antioxidant and anti-inflammatory properties exhibited radioprotective effects to maintain the integrity of cells against oxidative stress-induced tissue damage (Shedid et al., 2019). Combinations of phytochemicals may offer additive or synergistic effects, which would enhance their efficacy at low doses making them potent treatment modalities to inhibit or eliminate tissue damage due to oxidative stress initiation.

Many medicinal plants have been used with no side effects and phytochemicals derived from them. Phytochemicals have been classified into six major categories based on their chemical structures and characteristics. These categories include carbohydrate, lipids, phenolics, terpenoids and alkaloids, and other nitrogen-containing compounds. Phenolics are the largest and most structurally varied group of phytochemicals, and this group includes the flavonoids and phenolic acids. Flavonoids include the largest and most versatile class (Saxena et al., 2013). The phenolic acids are types of aromatic acid compound containing hydroxybenzoic acids and hydroxycinnamic acids that originate from non-phenolic molecules of benzoic and cinnamic acid, respectively (Machu et al., 2015). Other important phytochemicals such as lectins, glucosinolates, terpenes, polysaccharides, carotenoids, and others have been documented (Campos-Vega and Oomah, 2013).

Phytochemicals possess many therapeutic properties such as anticarcinogenic (Thomas et al., 2015), antimutagenic (Batista et al., 2016), anti-inflammatory (Oliviero et al., 2018), and antioxidant (Choi et al., 2012) effects. Some phytochemicals are known to block the action of enzymes and other substances that promote the growth of cancer cells (Athar et al., 2009). Additionally, phytochemicals such as thymoquinone, olive phenolics are known to have antimicrobial through inhibition of the action of ATP synthase, where the enzyme synthase could be used as a molecular target for these phytochemicals (Ahmad et al., 2015; Liu et al., 2017) Moreover, phytochemicals have the ability to protect against nephrotoxicity (Hassan et al., 2017a; Hassan et al., 2019), and hepatic oxidative injury (Hassan et al., 2018). Also, it is well documented that phytochemicals such as silybin, curcumin (CUR), genistein, ellagic acid, silymarin (SLM), and isothiocynates appear to protect against oxidative stress hazards (Hassan et al., 2017b; Prasad et al., 2016).

Curcumin, (1, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a yellow crystalline powder from turmeric (Curcuma longa L.). It possesses a wide range of pharmacological properties against multiple chronic diseases (Kunnumakkara et al., 2017). Curcumin has shown to inhibit inflammatory processes and considers as a powerful scavenger of the ROS and reactive nitrogen species (RNS) as well as being able to preserve the renal mitochondrial redox balance during acute and chronic nephrotoxicity (Trujillo et al., 2013). Further, Kim et al. (2016); Hashish and Elgaml (2016); Ghoniem et al. (2012) recorded the protective effects of CUR on renal function and oxidative stress.

Silymarin (SLM) is used for hepatic tissues in traditional medicine. It is a flavonoid extracted from Silybum marianum (milk thistle) plant, useful as a protective agent in various clinical and both in-vivo and in-vitro experimental models of hepatotoxicity (Gad, 2017), cardiotoxicity (Avci et al., 2017) and nephrotoxicity (Nouri and Heidarian, 2019). SLM is safe in animal models and no significant adverse reactions are reported in human studies (Hogan et al., 2007; Ahmed et al., 2019). SLM in combination with CUR has shown inhibitory effects against liver diseases and colon cancer cells (Gad, 2017; Montgomery et al., 2016).

The purpose of this study was to investigate the mitigating effects of CUR and SLM alone or in combination against IR-induced nephrotoxicity by assessment biochemical indices and the histological changes in the kidney tissue of male rats.